EPZ-011989

Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated.

In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Focusing on histone deacetylase (HDAC) inhibitors, we studied the mechanism of action of this class of agents, its effect on growth factor receptor regulation, and changes in epithelial-to-mesenchymal transition by using cell- and RT-qPCR-based assays.

Pan-HDAC inhibitor panobinostat exhibited potent anti-proliferative activity at low nanomolar concentrations in A204 rhabdoid tumor, and VAESBJ/GRU1 epithelioid sarcoma cell lines, strongly induced apoptosis, and resulted in significant tumor growth inhibition in VAESBJ xenografts. It differentially regulated EGFR, FGFR1 and FGFR2, leading to downregulation of EGFR in epithelioid sarcoma and to mesenchymal-to-epithelial transition whereas in rhabdoid tumor cells, EGFR was strongly upregulated and reinforced the mesenchymal phenotype. All three cell lines were rendered more susceptible towards combination with EGFF inhibitor erlotinib, further enhancing apoptosis.

HDAC inhibitors exhibit significant anticancer activity due to their multifaceted actions on cytotoxicity, differentiation and drug sensitization. Our data suggest that the tailored, tissue-specific combination of HDAC inhibitors with therapeutics which target cellular salvage mechanisms might increase their therapeutic relevance.

The signaling lymphocytic activation mol. F7 (CS-1) enables the selective killing of the myeloma cells with minimal side effects on the healthy tissue.In this study, we have modelled the 3D structure of CS-1 followed by performing mol. dynamic simulations.To develop a potential CS-1 modulator, a virtual screening of the 'Bioactive Compound Database'was conducted.The screening results have given three interacting regions.The best representative structure of each class and mode of action were revealed.Our study suggests compounds ICG-001, Avanafil, and BPTES, as novel drug candidates at the CS-1 protein target.The mol. dynamic simulation study reveals that the resulted compounds provide different binding patterns over the CS-1 Ig-like V-type domain in which Avanafil and BPTES provide stable interactions with their binding environment located at the bc-hi loops clefts and bc-fg loops clefts, resp.In contrast, compound ICG-001 shows more flexible and transient non-binding interaction due to the vast binding region over β-sheet strands consisting of H, C and D during the simulation timeline.We conclude that the identified compounds seem to be the best candidates to design a series of new compounds with the ability to bind to CS-1 with potential binding activity to its target.